It is known that certain mevalonate derivatives are active as anti-hyper-cholesterolemic agents, and these function by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. Lovastatin, Pravastatin, Simvastatin, Mevastatin, Atorvastatin and derivatives and analogs thereof are known as HMG-COA reductase inhibitors and are used as anti-hypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus; others are obtained by treating the fermentation products using the method of chemical synthesis or they are the product of total chemical synthesis.
Lovastatin is the first of the statins to be used widely and is manufactured by a fermentation-based process. It is produced as a secondary metabolite of the fungus Aspergillus terreus (U.S. Pat. No. 4,231,938) deposited in American Type Culture Collection under Nos. ATCC 20541 and ATCC 20542, and Monascus ruber deposited in Fermentation Research Institute Agency of Industrial Science and Technology, Ministry of International Trade and Industry, Japan (DE 3006216 Al) under No. Ferm. 4822.
Chemically lovastatin is 1,2,6,7,8,8a-hexahydro-β,δ-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene heptanoic acid δ-lactone of Formula I:

An active form of lovastatin is an acid, which is chemically 1,2,6,7,8,8a-hexahydro-β,δ-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene heptanoic acid of Formula II:

The recent commercial introduction of chemically synthesised HMG-CoA reductase inhibitors has provided a need for the development of high yielding processes for production of fermentation-based statins. The techniques to improve the processes include, but are not limited to, improving the producer microorganism, scale-up of the process, improving the culture medium or simplifying the downstream recovery process.
In the fermentation broth, lovastatin is present mostly in its hydroxy acid form, mevinolinic acid. The isolation of lovastatin from the fermentation broth, can be categorised into two routes in the prior art processes. The first route comprises of solvent extraction of mevinolinic acid and isolation of ammonium salt of mevinolinic acid as an intermediate and its further lactonization to lovastatin (U.S. Pat. No. 4,319,039).
The second route comprises of solvent extraction of mevinolinic acid, lactonization in the solvent phase and isolation as lovastatin (PCT publication WO 97/20834). The isolation of lovastatin as disclosed in EP 033536 comprises of extraction of the broth with ethyl acetate. The extract is concentrated by vacuum distillation followed by lactonization in toluene at 106° C. for 2 hours. After the lactonization is complete, the solution is concentrated to a small volume and then subjected to column chromatography using solvents like ethyl acetate or n-hexane and the collected fractions are again concentrated in vacuum and then pure lovastatin crystallizes in the lactone form.
Both the routes may employ a final purification step to obtain lovastatin of pharmacopoeial grade.
The process for the isolation and purification of anti-hypercholesterolemic agents disclosed in the earlier patents have certain inherent disadvantages and involves a number of steps which include multiple solvent extractions, chromatography, lactonization and crystallization methods. Although, the purity of the final product obtained by these procedures is of pharmacopoeial standards yet, the yields of the desired product are relatively low. In addition, they require both large amounts of organic solvents and correspondingly large equipment suited for these quantities. The second route involves lactonization at higher temperature in the solvent phase necessitating elaborate purification step(s) for removal of undesirable impurities generated during the lactonization step.
Neither of the methods heretofore described is completely satisfactory for the above-stated reasons.